Wacław Kuczmik

Rapamycin induces of protective autophagy in vascular endothelial cells exposed to oxygen-glucose deprivation.

The protective potential of rapamycin has been reported in a few experimental models of brain ischemia, both in vivo and in vitro. Although the precise cellular processes underlying the neuroprotective effects of rapamycin in experimental models of stroke remain unknown, the current experimental data suggest that the mechanism of action of the drug may result from the mTOR-mediated autophagy induction. However, it is unclear whether the activation of autophagy acts as a pro-death or pro-survival factor in vascular endothelial cells in ischemic brain damage. It seems to be very important, since stroke affects not only neurons and astrocytes but also microvessels. In the present study, we used human umbilical vein endothelial cells (HUVEC) subjected to ischemia-simulating conditions (combined oxygen and glucose deprivation, OGD) for 6h to determine potential effect of rapamycin-induced autophagy on HUVEC damage. The drug at concentrations of 100 and 1000nM increased the expression of Beclin 1 and LC3-II together with a significant increase in the p62 degradation in ischemic HUVEC. Treatment with rapamycin in OGD significantly increased the cell viability, indicating that the drug exerts cytoprotective effect. The inhibition of Beclin 1 by siRNAs significantly attenuated the expression of autophagy-related proteins and reduced HUVEC viability following OGD and rapamycin treatment. Our findings demonstrated that toxicity of simulated ischemia conditions were enhanced in HUVEC when autophagy was blocked, and that rapamycin effectively prevented OGD-evoked damage by induction of protective autophagy via inhibition of the mTOR pathway.

Mobilization of CD34+CXCR4+ Stem/Progenitor Cells and the Parameters of Left Ventricular Function and Remodeling in 1-Year Follow-up of Patients with Acute Myocardial Infarction

Mobilization of stem cells in acute MI might signify the reparatory response. Aim of the Study. Prospective evaluation of correlation between CD34+CXCR4+ cell mobilization and improvement of LVEF and remodeling in patients with acute MI in 1-year followup. Methods. 50 patients with MI, 28 with stable angina (SAP), and 20 individuals with no CAD (CTRL). CD34+CXCR4+ cells, SDF-1, G-CSF, troponin I (TnI) and NT-proBNP were measured on admission and 1 year after MI. Echocardiography and ergospirometry were carried out after 1 year. Results. Number of CD34+CXCR4+ cells in acute MI was significantly higher in comparison with SAP and CTRL, but lower in patients with decreased LVEF ≤40%. In patients who had significant LVEF increase ≥5% in 1 year FU the number of cells in acute MI was significantly higher versus patients with no LVEF improvement. Number of cells was positively correlated (r = 0,41, P = 0,031) with absolute LVEF change and inversely with absolute change of ESD and EDD in 1-year FU. Mobilization of CD34+CXCR4+ cells in acute MI was negatively correlated with maximum TnI and NT-proBNP levels. Conclusion. Mobilization of CD34+CXCR4+ cells in acute MI shows significant positive correlation with improvement of LVEF after 1 year.

Neck duplex Doppler ultrasound evaluation for assessing chronic cerebrospinal venous insufficiency in multiple sclerosis patients

Introduction: Recent clinical studies have suggested a relationship between multiple sclerosis (MS) and the occurrence of pathological changes in the jugular, vertebral and azygous veins that result in abnormal blood outflow from the brain and the spinal cord. Together, these pathological changes have been designated chronic cerebrospinal venous insufficiency (CCSVI). The aim of the present study was to evaluate the usefulness of duplex Doppler ultrasound in the evaluation of central nervous system venous outflow disturbances in patients suffering from MS. Methods: We examined 181 patients with MS, diagnosed on the basis of the McDonald criteria, and 50 healthy volunteer controls. All patients underwent Doppler ultrasound examination of the internal jugular veins (IJV) and vertebral veins (VVs). The presence of outflow disturbances and morphological abnormalities were evaluated. Results: Pathological changes in the extracranial jugular veins were diagnosed in 148/181 MS patients (82%) and 7/50 control group volunteers (14%). The following abnormalities in the MS group were revealed: the presence of a reflux in the IJVs and/or VVs (54%), narrowing (54%), a complete block in the flow through the IJV (10%) and an abnormal postural control of the cerebral outflow route (25%). These particular pathologies were of statistical significance in the MS group compared with the control group. This study also revealed a correlation between the occurrence of inverted flow in patients in a sitting position and chronic progressive MS (P = 0.0033). Conclusions: The examinations undertaken indicate a possible connection between MS and CCSVI. The widely accessible and highly sensitive and specific Doppler ultrasound test may be useful for revealing, and preliminary analysis of, CCSVI pathologies.

Self-expandable metallic stents in the treatment of post-esophagogastrostomy/post-esophagoenterostomy fistula

SUMMARY.  Esophageus or gaster resection in patients with malignant disease is still a treatment of choice. It is obvious that each surgical procedure in these patients carries some possibility of complications. Esophageo-gastric or esophageo-jejuno anastomosis has a 4–27% frequency of fistula occurrence. All these result in 65% mortality in cases of poorer prognosis. The aim of this paper is not to present all types of complications but to objectively analyse the usefulness of the covered stent placement in the treatment of anastomotic fistulas. We present six patients who were treated for postoperative fistula of esophageo-gastric anastomosis (1 case) or esophageo-jejuno anastomosis (5 cases). All patients were treated with stapler suture for digestive tract reconstruction after malignancy removal during the primary surgical procedure. Signs and symptoms of suture leak between 5–8 days post-surgery were observed. Conservative therapy was not effective. Thus a new method of treatment was employed – covered stent placement. The procedure was performed under X-ray control. In all treated patients there was change for the better and quick reduction of secretion from the fistulas was observed. All patients were discharged from the department after several days and all had survived at 30 days follow-up. Covered esophageal stent placement seems to be a safe and promising method of treatment for patients with anastomotic fistula which significantly reduces mortality and improves quality of live. Our experiences confirms that of other investigators.

Effects of intracoronary delivery of allogenic bone marrow-derived stem cells expressing heme oxygenase-1 on myocardial reperfusion injury

Heme oxygenase-1 (HO-1) decreases apoptosis, inflammation and oxidative stress. The aim of the study was to investigate the effects of intracoronary infusion of allogenic bone marrow cells (BMC) overexpressing HO-1 in the porcine model of myocardial infarction (MI). MI was produced by balloon occlusion of a coronary artery. BMC were transduced with adenoviruses encoding for HO-1 (HO-1 BMC) or GFP (GFP-BMC) genes. Prior to reperfusion animals received HO-1 BMC, control BMC (unmodified or GFP-BMC) or placebo. Left ventricular (LV) ejection fraction (EF), shortening fraction (SF), end-systolic and end-diastolic diameters (EDD, ESD) were assessed by echocardiography before, 30 minutes (min) and 14 days after reperfusion. BMC significantly improved LVEF and SF early (30 min) after reperfusion as well as after 14 days. Early after reperfusion HO-1 BMC were significantly more effective than control BMC, but after 14 days, there were no differences. There were no effect of cells on LV remodelling and diastolic function. Both HO-1 BMC and control BMC significantly reduced the infarct size vs. placebo (17.2 ± 2.7 and 18.8 ± 2.5, respectively, vs. 27.5 ± 5.1, p= 0.02) in histomorphometry. HO-1-positive donor BMC were detected in the infarct border area in pigs receiving HO-1-cells. No significant differences in expression of inflammatory genes (SDF-1, TNF-α, IL-6, miR21, miR29a and miR133a) in the myocardium were found. In conclusion, intracoronary delivery of allogeneic BMC immediately prior to reperfusion improved the LVEF and reduced the infarct size. HO-1 BMC were not superior to control cells after 14 days, however, produced faster recovery of LVEF. Transplanted cells survived in the peri-infarct zone.

Effects of Trans-Endocardial Delivery of Bone Marrow-Derived CD133+ Cells on Left Ventricle Perfusion and Function in Patients With Refractory Angina: Final Results of Randomized, Double-Blinded, Placebo-Controlled REGENT-VSEL Trial.

Rationale: New therapies for refractory angina are needed. Objective: Assessment of transendocardial delivery of bone marrow CD133+ cells in patients with refractory angina. Methods and Results: Randomized, double-blinded, placebo-controlled trial enrolled 31 patients with recurrent Canadian Cardiovascular Society II–IV angina, despite optimal medical therapy, ≥1 myocardial segment with inducible ischemia in Tc-99m SPECT who underwent bone marrow biopsy and were allocated to cells (n=16) or placebo (n=15). Primary end point was absolute change in myocardial ischemia by SPECT. Secondary end points were left ventricular function and volumes by magnetic resonance imaging and angina severity. After 4 months, there were no significant differences in extent of inducible ischemia between groups (summed difference score mean [±SD]: 2.60 [2.6] versus 3.63 [3.6], P=0.52; total perfusion deficit: 3.60 [3.6] versus 5.01 [4.3], P=0.32; absolute changes of summed difference score: −1.38 [5.2] versus −0.73 [1.9], P=0.65; and total perfusion deficit: −1.33 [3.3] versus −2.19 [6.6], P=0.65). There was a significant reduction of left ventricular volumes (end-systolic volume: −4.3 [11.3] versus 7.4 [11.8], P=0.02; end-diastolic volume: −9.1 [14.9] versus 7.4 [15.8], P=0.02) and no significant change of left ventricular ejection fraction in the cell group. There was no difference in number of patients showing improvement of ≥1 Canadian Cardiovascular Society class after 1 (41.7% versus 58.3%; P=0.68), 4 (50% versus 33.3%; P=0.63), 6 (70% versus 50.0%; P=0.42), and 12 months (55.6% versus 81.8%; P=0.33) and use of nitrates after 12 months. Conclusion: Transendocardial CD133+ cell therapy was safe. Study was underpowered to conclusively validate the efficacy, but it did not show a significant reduction of myocardial ischemia and angina versus placebo. Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01660581.

Tension-Free Vaginal Tape, Transobturator Tape, and Own Modification of Transobturator Tape in the Treatment of Female Stress Urinary Incontinence: Comparative Analysis

Introduction. This study is a comparative evaluation of the TVT, TOT, and our own modification of TOT (mTOT) in the treatment of female stress urinary incontinence from a single center experience. Material and Methods. The study was conducted on 527 patients with SUI diagnosed on the basis of urodynamic studies. They were divided into three groups—TVT: n = 142, (TOT): n = 129, and mTOT: n = 256. All of the patients underwent evaluation at 1, 3, and 6 months after surgery. Results were statistically analysed and compared. Results. Objective and subjective effectiveness after the surgery were not significantly different in the study groups and ranged from 90.1% to 96.4%. Mean surgery time was 32.3, 28.2, and 26.4 in the TVT, TOT, and mTOT, respectively. Mean hospitalization time was 2.51 days. Mean catheter maintenance time was significantly higher in the TVT than in other groups. In the TVT group total incidence of complications was 13.4%, and it was significantly higher than that in TOT and mTOT (9.3% and 8.6%, resp.). Conclusions. TVT, TOT, and mTOT are highly effective and safe methods in the treatment of SUI. There are no differences in the efficacy between the methods with a little higher percentage of complications in the TVT group.

Effects of Transendocardial Delivery of Bone Marrow–Derived CD133 + Cells on Left Ventricle Perfusion and Function in Patients With Refractory Angina

Rationale: New therapies for refractory angina are needed. Objective: Assessment of transendocardial delivery of bone marrow CD133+ cells in patients with refractory angina. Methods and Results: Randomized, double-blinded, placebo-controlled trial enrolled 31 patients with recurrent Canadian Cardiovascular Society II–IV angina, despite optimal medical therapy, ≥1 myocardial segment with inducible ischemia in Tc-99m SPECT who underwent bone marrow biopsy and were allocated to cells (n=16) or placebo (n=15). Primary end point was absolute change in myocardial ischemia by SPECT. Secondary end points were left ventricular function and volumes by magnetic resonance imaging and angina severity. After 4 months, there were no significant differences in extent of inducible ischemia between groups (summed difference score mean [±SD]: 2.60 [2.6] versus 3.63 [3.6], P=0.52; total perfusion deficit: 3.60 [3.6] versus 5.01 [4.3], P=0.32; absolute changes of summed difference score: −1.38 [5.2] versus −0.73 [1.9], P=0.65; and total perfusion deficit: −1.33 [3.3] versus −2.19 [6.6], P=0.65). There was a significant reduction of left ventricular volumes (end-systolic volume: −4.3 [11.3] versus 7.4 [11.8], P=0.02; end-diastolic volume: −9.1 [14.9] versus 7.4 [15.8], P=0.02) and no significant change of left ventricular ejection fraction in the cell group. There was no difference in number of patients showing improvement of ≥1 Canadian Cardiovascular Society class after 1 (41.7% versus 58.3%; P=0.68), 4 (50% versus 33.3%; P=0.63), 6 (70% versus 50.0%; P=0.42), and 12 months (55.6% versus 81.8%; P=0.33) and use of nitrates after 12 months. Conclusion: Transendocardial CD133+ cell therapy was safe. Study was underpowered to conclusively validate the efficacy, but it did not show a significant reduction of myocardial ischemia and angina versus placebo. Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01660581.

The influence of atmospheric pressure on aortic aneurysm rupture — is the diameter of the aneurysm important?

BACKGROUND The rate of aortic aneurysm rupture correlates with the aneurysms diameter, and a higher rate of rupture is observed in patients with larger aneurysms. According to the literature, contradictory results concerning the relationship between atmospheric pressure and aneurysm size have been reported. AIM In this paper, we assessed the influence of changes in atmospheric pressure on abdominal aneurysm ruptures in relationship to the aneurysms size. METHODS The records of 223 patients with ruptured abdominal aneurysms were evaluated. All of the patients had been admitted to the department in the period 1997-2007 from the Silesia region. The atmospheric pressures on the day of the rupture and on the days both before the rupture and between the rupture events were compared. The size of the aneurysm was also considered in the analysis. RESULTS There were no statistically significant differences in pressure between the days of rupture and the remainder of the days within an analysed period. The highest frequency of the admission of patients with a ruptured aortic aneurysm was observed during periods of winter and spring, when the highest mean values of atmospheric pressure were observed; however, this observation was not statistically confirmed. A statistically non-significant trend towards the higher rupture of large aneurysms (> 7 cm) was observed in the cases where the pressure increased between the day before the rupture and the day of the rupture. This trend was particularly pronounced in patients suffering from hypertension (p = 0.1). CONCLUSIONS The results of this study do not support the hypothesis that there is a direct link between atmospheric pressure values and abdominal aortic aneurysm ruptures.

Duplex Doppler ultrasound examination of extremities arteries: guidelines of the Polish Society for Vascular Surgery

The duplex Doppler examination of extremities arteries is the primary diagnostic method in detecting disorders leading to lower and upper extremities blood supply disturbances. In many cases the Doppler ultrasound plays a major role in the process of qualification to the reconstructive procedures or conservative treatment, especially to the endovascular procedures. Regardless of the widespread availability and high sensitivity and specificity of this method its burdened with serious drawbacks. The most important of them are evaluation subjectivity and variety of methods determining the haemodynamic stenosis consequences. They often cause difficulties in comparing the test results carried out in different centres and to find correlations with other imaging methods results. In order to overcome these drawbacks, Polish Society for Vascular Surgery has attempted to develop recommendations for uniform methodology of extremities arteries Doppler examination. Legal terms, the manner of examination and its interpretation were presented. Proposing the way of highlights results and messages conclusion to enable the recommendations implementation of endovascular and surgical qualifications relating to surgical treatment. We hope that these recommendations will help to standardise examination techniques.